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=Thymidylate Synthase= Thymidylate Synthase is a protein found in all organisms that make DNA. Thymidylate Synthase (TS) is the essential enzyme that catalyzes the formation of dTMP from dUMP, using 5,10-methylenetetrahydrofolate (mTHF) as a cosubstrate.

Overview
Thymidylate Synthase catalyzes the reductive methylation of deoxyuridylic acid during the de novo synthesis of thymidylic acid. This reaction occurs primarily during the S phase of the cell cycle. Thymidylate synthase is an essential enzyme in proliferating cells that are not supplied with an alternate source of thymidine nucleotides. Research has shown that thymidylate synthase enzyme levels are much higher in rapidly proliferating cells than in non dividing cells. 

Mammalian Thymidylate Synthase
Human and other mammalian thymidylate synthase enzyme have a N-terminal extension of aprox 27 amino acids. This extension is not present in bacterial thymidylate synthase. The extension is believed to play a primary role in protein turnover however not in catalytic activity.

Mechanism of Thymidylate Synthase Initiation
Thymidylate synthase converts dUMP to dTMP and is labeled as the rate-limiting enzyme in the synthesis of pyrimidine nucleotides, which are required for DNA synthesis. The conversion of dUMP to dTMP is done with a cosubstrate mTHF. The reaction is initiated by the active site cysteine, Cys195, is attacked by C6 of dUMP and this leads to the formation of C5 of dUMP. The formation generates a second covalent bond between dUMP and mTHF and eventually a ternary catalytic complex. The role of Lipids (Figure. 1) in the conversion of dUMP to dTMP can be important to proper structure and interactions that are required to initiate the formation of C5 dUMP.

Exploring the Structure
The native thymidylate synthase enzyme is made up of a dimer of identical subunits. The dimer interaction is formed by an association between five-stranded B-sheets present in each monomer. Residues from both subunits are involved in each active site. During the process of converting dUMP to dTMP thymidylate synthase enzyme-complex consists of a crystallized binary complex, containing a nucleotide analog and a ternary complex containing dUMP and a folate analog.

Significance
The importance of thymidylate synthase as shown in Figure 2, is the essential role it plays in the reproduction of DNA. From a medical prospective, thymidylate synthase has been an important target in the chemotherapy of colon cancer and some other malignancies.